Primary colorectal cancer (PCRC) is a common digestive tract cancer in the elderly. However, the treatment effect of PCRC is still limited, and the long-term survival rate is low. Therefore, further exploring the pathogenesis of PCRC, and searching for specific molecular targets for diagnosis are the development trends of precise medical treatment, which have important clinical significance. The public data were downloaded from Gene Expression Omnibus (GEO) database. Verification for repeatability of intra-group data was performed by Pearson's correlation test and principal component analysis. Differentially expressed genes (DEGs) between normal and PCRC were identified, and the protein-protein interaction (PPI) network was constructed. Significant module and hub genes were found in the PPI network. A total of 192 PCRC patients were recruited between 2010 and 2019 from the Fourth Hospital of Hebei Medical University. RT-PCR was used to measure the relative expression of CLCA4 and MS4A12. Furthermore, the study explored the effect of expression of CLCA4 and MS4A12 for overall survival. A total of 53 DEGs were identified between PCRC and normal colorectal tissues. Ten hub genes concerned to PCRC were screened, namely CLCA4, GUCA2A, GCG, SST, MS4A12, PLP1, CHGA, PYY, VIP, and GUCA2B. The PCRC patients with low expression of CLCA4 and MS4A12 has a worse overall survival than high expression of CLCA4 and MS4A12 (P<0.05). The research of DEGs in PCRC (53 DEGs, 10 hub genes, especially CLCA4 and MS4A12) and related signaling pathways is conducive to the differential analysis of the molecular mechanism of PCRC. © 2020 The Author(s).